More than 30% of patients with epilepsy have inadequate control of seizures despite the choice of an adequate antiepileptic drug (AED) and carefully monitored treatment. Pharmacoresistant epilepsy is a major health problem, associated with increased morbidity and mortality, and accounting for much of the economic burden of epilepsy. A striking obstacle in developing new strategies for treatment of pharmacoresistant epilepsy is that mechanisms of pharmacoresistance are only poorly understood. Despite the problem of intractable epilepsy, there are only few models specifically dedicated to identify effective therapeutic agents for resistant epilepsy or to study mechanisms of drug resistance. Thus, new methods for evaluating the therapeutic potential of novel compounds for the treatment of refractory epilepsy are urgently needed. An animal model of epilepsy allowing selection of pharmacoresistant and pharmacosensitive subgroups of animals would be particularly valuable to study mechanisms of intractability and to develop more efficacious treatment strategies. The specific aim of this proposal is to study whether AED non-responders and responders can be selected by prolonged drug treatment from rat models of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures. Two models in which spontaneous recurrent seizures develop after either chemical or electrical induction of a status epilepticus will be examined in this respect. In each model, two to three AED will be daily administered at anticonvulsant doses for two weeks and drug plasma levels are controlled over this period. For comparison with the treatment period, each rat is recorded two weeks before and after the drug treatment, resulting in a length of each drug trial of six weeks. Rats with persistent seizure activity not responding or with very poor response to at least two AED at maximum tolerated doses are considered pharmacoresistant. Our goal is to establish standard assays that can be employed by researchers to continue the search for treatments of drug resistant epilepsy. [unreadable] [unreadable]